Cardiovascular disease (CVD) is the major cause of mortality for patients with chronic kidney disease (CKD). Cardiac hypertrophy, occurring in up to 95% patients with CKD (also known as uremic cardiomyopathy), increases their risk for cardiovascular death. Many CKD-specific risk factors of uremic cardiomyopathy have been recognized, such as secondary hyperparathyroidism, indoxyl sulfate (IS)/p-cresyl, and vitamin D deficiency. However, several randomized controlled trials have recently shown that these risk factors have little impact on the mortality of CVD. Klotho is a type 1 membrane protein predominantly produced in the kidney, and CKD is known to be a Klotho-deficient state. Because of its important role in FGF23 and phosphate metabolism, Klotho is believed to affect cardiac growth and function indirectly through FGF23 and phosphate. Recent studies showed that soluble Klotho protects the heart against stress-induced cardiac hypertrophy by inhibiting TRPC6 channel-mediated abnormal Ca2+ signaling in the heart, and the decreased level of circulating soluble Klotho in CKD is an important cause of uremic cardiomyopathy independent of FGF23 and phosphate. These new evidence suggested that Klotho is an independent contributing factor for uremic cardiomyopathy and a possible new target for treatment of this disease.